1. Field of the Invention
The invention pertains to a method of treating or preventing neuronial damage through the potent neuroprotectants and anxiolytics which achieve their action through the antagonism of specific excitatory amino acid (EAA) neurotransmitter receptors. More particularly, the invention is directed to the use of 2-amino-.omega.-phosphonoalkanoic acids bearing a cycloalkyl group bridging adjacent carbons on the alkyl chain and their pharmaceutically acceptable salts and derivatives, as neuroprotectants and anxiolytics.
2. Description of the Prior Art
Three major types of receptors for excitatory amino acids (EAA) have been identified in the mammalian central nervous system (CNS). Originally designated according to agonist responses, these include sites activated by the pyrrolidine neurotoxin kainic acid, the conformationally restricted glutamate analog, quisqualic acid and the synthetic aspartate analog, N-methyl-D-aspartic acid (NMDA) [Watkins and Evans, R. H.: Excitatory Amino Acid Transmitters. Ann. Rev. Pharmacol. Toxicol. 21:165-204, 1981; Foster and Fagg, Acidic Amino Acid Binding In Mammalian Neuronal Membranes: Their Characteristics And Relationships to Synaptic Receptors. Br. Res. Rev. 7:103-184, 1984; Ferkany, Receptors For Excitatory Amino Acids: Ligand Binding and Functional Assays. In Receptor Pharmacology and Function, ed. by M. Williams, R. Glennon and B. M. Timmermans, Marcel Dekker, Inc., New York, N.Y. pp. 415-452, 1988]. Specific and potent antagonists of EAA-mediated neurotransmission have been identified only for the latter recognition site and, accordingly, our understanding of the functional role of NMDA receptors in physiological and pathological conditions is most advanced.
To date, NMDA receptors have been implicated in a variety of CNS processes including learning and memory [Morris et al., Selective Impairment of Learning and Blockade of Long-Term Potentiation by an N-Mehtyl-D-Aspartate Receptor Antagonist, AP5. Nature 319:774-776, 1986; Pontecorvo and Clissold, NMDA Antagonism and Working Memory Performance. Soc. Neurosci. Abs. 14:101.2, 1988: epilepsy [Croucher et al., Anticonvulsant Action of Excitatory Amino Acid Antagonists. Science 216:899-901, 1982: Schwarcz and Ben-Ari, eds. Excitatory Amino Acids and Epilepsy, Plenum Press, New York, N.Y., 1986], nociception [Raigordsky and Urca, Intrathecal N-Methyl-D-Aspartate (NMDA) Activates Both Nociceptive and Antinociceptive Systems. Br. Res. 422:158-162, 1987], neurodegenerative disorders [Foster et al., On the Excitotoxic Properties of Quinolinic Acid, 2,3-Piperidine Dicarboxylic Acids and Structurally Related Compounds. Neuropharmacol. 22:1331-1342, 1983: Greenamyre et al., Alterations in L-Glutamate Binding Sites in Alzheimer's and Huntington's Diseases. Science 227:1496-1499, 1984: Young et al., NMDA Receptor Losses in Putamen From Patients With Huntington's Disease. Science 241:981-983, 1987], dementia [Greenamyre et al., Dementia of the Alzheimer's Type: Changes in Hippocampal L-[3H]Glutamate Binding. J. Neurochem. 48:543-551, 1987: Geddes et al., Density and Distribution of NMDA Receptors in the Human Hippocampus in Alzheimer's Disease. Br. Res. 399:156-161, 1986], and the neuronal damage seen following hypoxia [Goldberg et al., N-Methyl-D-Aspartate Receptors Mediate Hypoxic Neuronal Injury in Cortical Culture. J. Pharmacol. Exp. Therap. 243:784-791, 1987: Clark and Rothman, Blockade of Excitatory Amino Acid Receptors Protects Anoxic Hippocampal Slices. Neurosci. 21:665-671, 1987], ischemia [Simon, et al., Blockade of N-Methyl-D-Aspartate Receptors May Protect Against Ischemic Damage in the Brain. Science 226:850-852, 1984] and hypoglycemia [Weiloch, Hypoglycemia-Induced Neuronal Damage Prevented By An N-Methyl-D-Aspartate Antagonist. Science 230:681 683, 1985].
Given this breadth of function, the proposal that NMDA receptor antagonists may provide a novel therapeutic method to intervene in CNS pathology is not surprising. However what is surprising is that prototypical antagonists such as DL(.+-.)2-amino-5-phosphonopentanoic acid and DL(.+-.)2-amino-7-phosphonoheptanoic acid, while proving useful to explore the basic characteristics of NMDA receptor-mediated neurotransmission, lack the potency and bioavailability to be useful in a clinical setting.
More recently, two approaches to develop therapeutically acceptable antagonists have been pursued. First, is the development of noncompetitive antagonists which inhibit neuroexcitation at either the NMDA receptor-associated ion channel [Anis et al., The Dissociative Anaesthetics Ketamine and Phencyclidine Reduce Excitation of Central Mammalian Neurons by N-Methyl Aspartate. Brit. J. Pharmacol. 79:565-575, 1983; Jarvis, et al., Quantitative Autoradiographic Localization of NMDA Receptors in Rat Brain Using [3H]CPP: Comparison With [3H]TCP Binding Sites. Eur. J. Pharmacol. 141:148-152, 1987] or the glycine-activated modulatory site [Johnson and Ascher, Glycine Potentiates the NMDA Response in Cultured Mouse Brain Neurons. Nature 325:529-531, 1987; Kleckner and Dingledine, Requirement for Glycine in Activation of NMDA Receptors Expressed in Xenopus Oocytes. Science 241:835-837, 1988]. Second, using the method of rational design, attempts have been made to develop potent, selective, competitive antagonists having substantial CNS bioavailability following systemic administration. Each approach has yielded promising compounds including the noncompetitive antagonist MK-801 [5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine] [Clineschmidt, et al., Anticonvulsant Activity of (+)-5-Methyl-10,11-Dihydro-5H-Dibenzo[a,d] Cyclohepten-5, 10 Imine (MK-801), a Substance With Potent Anticonvulsant, Central, Sympathomimetic, and Apparent Anxiolytic Properties. Drug Dev. Res. 2:123-134, 1982; Wong et al., The Anticonvulsant MK-801 is a Potent N-Methyl-D-Aspartate Antagonist. Proc. Nat. Acad. Sci. (USA) 83:7104-7108, 1986; Kemp, et al., Non-Competitive Antagonists of Excitatory Amino Acid Receptors. Tr. Neurosci. 10:294-298, 1987], as well as the competitive receptor blockers CPP [3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid] [Olverman, et al., [3H]CPP, A New Competitive Ligand for NMDA Receptors. Eur. J. Pharmacol. 131:161-162, 1986; Lehmann, et al., A Selective N-Methyl-D-Aspartate (NMDA)-Type Receptor Antagonist: Characterization in Vitro and in Vivo. J. Pharmacol. Exp. Therap. 240:737-746, 1987; Chapman, et al., Anticonvulsant Action and Biochemical Effects in DBA/2 Mice of CPP (3-(+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate), A Novel N-Methyl-D-Aspartate Antagonist. Eur. J. Pharmacol. 139:91-96,1987], CGS 19755 [4-phosphonomethyl-2-piperidinecarboxylic acid] [Boast, et al., A Comparison of Two N-Methyl-D-Aspartate Antagonists. See. Neurosci. Abs. 13:497, 1987; Lehmann, et al., CGS 19755, A Selective and Competitive N-Methyl-D-Aspartate-Type Excitatory Amino Acid Receptor Antagonist. J. Pharmacol Exp. Therap. 246: 1988] and [2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid [Ferkany et al., submitted]. For example, it has been shown in U.S. Pat. No. 4,761,405 and Ferkany, et al., Pharmacological Profile of NPC 12626, A Novel, Competitive N-Methyl-D-Aspartate Receptor Antagonist, J. Pharmac. Exp. Ther. (Submitted), that [NPC 12626] 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid selectively inhibits ligand binding to NMDA receptors in vitro and that the compound is a potent anticonvulsant in animal models of epilepsy.